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Not yet recruitingNCT07875972Updated Oct 15, 2026

Safety, Tolerability, and Pharmacodynamic Exploration of Orelabrutinib in Patients With Amyotrophic Lateral Sclerosis (ALS)

A Phase 1 interventional study of Orelabrutinib in Amyotrophic Lateral Sclerosis (ALS), sponsored by Liu Qing. Not yet recruiting. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2026-10-15.

Sponsored by Liu Qing · Phase 1, Interventional, and Treatment

Updated Oct 15, 2026Newly registeredGo to Updates ↓
Phase
Phase 1
Study type
Interventional
Enrollment
12
Allocation
Non-randomized
Ages
18 Years to 75 Years
Sex
All
01

Study summary

This is a single-center, open-label, dose-escalation, investigator-initiated pilot study to evaluate the safety, tolerability, dose-limiting toxicity (DLT), and pharmacodynamic signals of orelabrutinib in patients with amyotrophic lateral sclerosis (ALS). A 12-week run-in observation period will be used to establish each participant's historical ALSFRS-R decline slope. Participants will receive orelabrutinib 50 mg once daily (QD), 100 mg QD, or optional 150 mg QD using a 3+3 dose-escalation design for 24 weeks, followed by a 4-week safety follow-up.

Read the detailed description

Orelabrutinib is an oral, irreversible, highly selective Bruton's tyrosine kinase (BTK) inhibitor. Preclinical studies suggest that BTK inhibition may suppress neuroinflammation and promote motor neuron survival through a "dual decoupling" mechanism. This study will assess safety and tolerability, pharmacokinetics (PK), BTK target occupancy, inflammatory biomarkers, and exploratory efficacy signals in patients with ALS.

02

Conditions studied

  • Amyotrophic Lateral Sclerosis (ALS)

Keywords

  • Amyotrophic Lateral Sclerosis
  • Orelabrutinib
  • BTK inhibitor
  • Neuroinflammation
  • Safety
  • Open-label
03

In context

Amyotrophic Lateral Sclerosis

1,000 studies on the registry are indexed under Amyotrophic Lateral Sclerosis; 284 are open to participants now.

This study's planned enrollment of 12 is below the median of 37 across 678 interventional studies indexed under Amyotrophic Lateral Sclerosis.

Browse Amyotrophic Lateral Sclerosis studies →

Lead sponsor

This is the only study on the registry with Liu Qing as lead sponsor.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 75 Years
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

  1. Age 18-75 years, either sex.
  2. Confirmed diagnosis of ALS by a neurologist according to the Gold Coast criteria or the revised El Escorial (Airlie House) criteria, with other diseases excluded.
  3. Duration from disease onset to enrollment no more than 36 months.
  4. ALSFRS-R score ≥ 35 at screening.
  5. FVC% predicted ≥ 70% and SVC% predicted ≥ 70%; no resting dyspnea, orthopnea, or need for long-term non-invasive ventilation/oxygen therapy.
  6. Participants are able to take medication orally and are independent of enteral nutrition support (e.g., PEG, gastric tube) at screening, as judged by the principal investigator.
  7. Stable-dose riluzole (≥ 30 days) and/or edaravone (stable use for one course) is permitted.
  8. Assessed as having full capacity to provide informed consent.

Exclusion criteria

Exclusion Criteria

  1. Tracheostomy or use of non-invasive ventilation (NIV) > 23 h/day.
  2. Abnormal liver function (ALT/AST ≥ 3×ULN), abnormal renal function (eGFR \< 60 mL/min/1.73 m²), absolute neutrophil count (ANC) ≤ 1.5×10⁹/L, platelet count ≤ 100×10⁹/L, or hemoglobin ≤ 100 g/L; international normalized ratio (INR) ≥ 1.5×ULN, activated partial thromboplastin time (APTT) ≥ 1.5×ULN.
  3. Unable to swallow or tolerate oral medication at screening.
  4. Prior or current malignancy.
  5. Known active HBV, HCV, or HIV infection, or any uncontrolled active systemic infection.
  6. Major surgery within 6 weeks before screening, or need for major surgery during the study period.
  7. Current clinically significant cardiovascular disease, including: NYHA class 3 or 4 heart disease, such as arrhythmia, congestive heart failure, or myocardial infarction, or left ventricular ejection fraction (LVEF) \< 50%; primary cardiomyopathy; history of clinically significant QTc prolongation, or QTc > 470 ms (women), QTc > 450 ms (men); uncontrolled hypertension.
  8. Bleeding disorders or active bleeding events within 3 months, or current use of anticoagulant/antiplatelet drugs.
  9. Diseases significantly affecting gastrointestinal function, such as dysphagia, chronic diarrhea, intestinal obstruction, or gastrectomy.
  10. Any history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severe pulmonary function impairment.
  11. Prior exposure to BTK pathway inhibitors.
  12. Current use of moderate or strong CYP3A inhibitors or strong CYP3A inducers that cannot be safely discontinued or replaced before screening; moderate CYP3A4 inducers require evaluation by a pharmacist and the investigator.
  13. Receipt of a live vaccine within 2 weeks or planned receipt of a live vaccine during the study period (Note: inactivated vaccines may be administered according to local regulations, but the vaccination time and AEs must be recorded).
  14. Substance abusers or alcohol abusers.
  15. Breastfeeding or pregnant women, or women of childbearing age who are unwilling to use contraceptive measures during the trial and for 180 days after the last dose of study drug.
  16. Unable to understand the informed consent form (ICF).
  17. Any other relevant medically significant condition that may pose a risk to the participant, interfere with safety assessments, or increase the risk of death during the trial.
05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Sequential assignment
Masking
None (open label)
Enrollment
12 participants (estimated)

Study arms

  • Experimental
    Cohort 1: Orelabrutinib 50 mg QD

    Participants receive orelabrutinib 50 mg orally once daily (QD) for 24 weeks.

    Drug: Orelabrutinib

  • Experimental
    Cohort 2: Orelabrutinib 100 mg QD

    Participants receive orelabrutinib 100 mg orally once daily (QD) for 24 weeks.

    Drug: Orelabrutinib

  • Experimental
    Cohort 3 (Optional): Orelabrutinib 150 mg QD

    Optional exploratory cohort. Participants receive orelabrutinib 150 mg orally once daily (QD) for 24 weeks.

    Drug: Orelabrutinib

Interventions

  • DrugOrelabrutinib

    Cohort 1 planned enrollment: 3 participants; may expand to 6 if 1/3 participants experience a dose-limiting toxicity (DLT). Cohort 2 planned enrollment: 3 participants. This cohort will be initiated only after Cohort 1 completes the 28-day DLT observation period and the DSMB approves dose escalation. Cohort 3 (Optional) planned enrollment: 3 participants. This cohort will be initiated only if Cohorts 1 and 2 are safe and if BTK target occupancy / PD signals suggest insufficient target coverage, with written DSMB approval. A traditional 3+3 dose-escalation design is used,. Dose-escalation rules: If 0/3 patients experience a DLT, escalate to the next dose level; if 1/3 patients experience a DLT, expand that dose level to 6 patients; if 1/6 patients experience a DLT, escalation may proceed, whereas if ≥2/6 patients experience a DLT, the dose is deemed intolerable and escalation must stop; if ≥2/3 patients experience a DLT, escalation must stop immediately.

06

What researchers measure

Primary outcomes

  1. Serious adverse event (SAE) incidence

    ICH-GCP definition

    Time frame: Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28

  2. Adverse event (AE) incidence and severity

    CTCAE v5.0 grading

    Time frame: Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28

  3. Dose-limiting toxicity (DLT)

    Time frame: Week 4

  4. Number of subjects who discontinue treatment prematurely

    Time frame: Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24

  5. Number of patients who discontinue treatment prematurely due to adverse events

    Time frame: Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24

  6. Number of patients with clinically significant abnormal laboratory and ancillary examinations (including routine laboratory tests, cardiac safety, infection markers, bleeding markers, and new-onset tumor examinations)

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24; tumor markers and echocardiography at Week 0, Week 4, Week 12, and Week 24; CT of the chest, abdomen, and pelvis at Week 0 and Week 24

Secondary outcomes

  1. Plasma Orelabrutinib concentration

    Time frame: Week 0 (pre-dose, 2 h, and 8 h); trough concentrations at Week 1, Week 4, Week 12, and Week 24

  2. Cerebrospinal fluid (CSF) Orelabrutinib concentration

    Time frame: Week 0 and Week 4 (optional; only if the subject consents and the procedure is considered safe)

  3. Peripheral blood PBMC BTK target occupancy (TOR %)

    Time frame: Week 0, Week 1, Week 4, Week 12, and Week 24

  4. Peripheral blood PBMC p-BTK level

    Time frame: Week 0, Week 4, Week 12, and Week 24

  5. Peripheral blood B-cell count

    Time frame: Week 0, Week 1, Week 4, Week 12, and Week 24

  6. ALSFRS-R score and its rate of change slope

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28

  7. Forced vital capacity (FVC)

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 8, Week 16, and Week 24

  8. Medical Research Council (MRC) Muscle Strength Score

    The Medical Research Council (MRC) Muscle Strength Score ranges from 0 to 5 (minimum value: 0, maximum value: 5). Higher scores indicate better muscle strength (a better outcome), while lower scores indicate worse muscle strength (a worse outcome).

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28

  9. Composite survival rate at 6 months of treatment(Composite endpoint of overall survival (defined as time to death from any cause) or respiratory insufficiency (defined as tracheostomy or daily use of non-invasive ventilation ≥22 hours for ≥10 consecutive

    Time frame: Week 24

  10. Change from baseline to the follow-up time point in ALSAQ-40 quality of life

    Time frame: Week -12, Week 0, Week 4, Week 12, and Week 24

  11. Slow vital capacity (SVC)

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 8, Week 16, and Week 24

  12. Cerebrospinal fluid (CSF)-to-plasma concentration ratio

    Time frame: Week 0 and Week 4 (optional; only if the subject consents and the procedure is considered safe)

  13. Change from baseline to the follow-up time point in EuroQol 5-Dimension (EQ-5D)

    Time frame: Week -12, Week 0, Week 4, Week 12, and Week 24

  14. Change from baseline to the follow-up time point in Mini-Mental State Examination (MMSE)

    Time frame: Week -12, Week 0, Week 4, Week 12, and Week 24

  15. Change from baseline to the follow-up time point in Edinburgh Cognitive and Behavioural ALS Screen (ECAS)

    Time frame: Week -12, Week 0, Week 4, Week 12, and Week 24

Other outcomes

  1. Plasma NfL

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 4, Week 12, and Week 24

  2. Plasma GFAP

    Time frame: Week 0, Week 4, Week 12, and Week 24

  3. Cerebrospinal fluid (CSF) NfL/pNfH

    Time frame: Week 0 and Week 4 (optional)

  4. Motor Unit Number Estimation (MUNE) Measurement

    Time frame: Week 0, Week 12, and Week 24

  5. Muscle MRI

    Time frame: Week 0 and Week 24

  6. DPA-714/GE-180 PET, or SV2A PET (optional)

    Time frame: Week 0 and Week 24

  7. Chest, abdomen and pelvis CT

    Time frame: Week 0 and Week 24

  8. Exfoliated cells in cerebrospinal fluid (CSF): p-STING

    Time frame: Week 0 and Week 4 (optional)

  9. Peripheral blood PBMC: p-FOXO3A (Thr32/Ser253)

    Time frame: Week 0, Week 4, Week 12, and Week 24

  10. Peripheral blood PBMC: p-AKT (Ser473)

    Time frame: Week 0, Week 4, Week 12, and Week 24

  11. Plasma + CSF: inflammatory cytokine profile (IL-1β, IL-6, TNF-α, IFN-β, CXCL10)

    Time frame: Week 0, Week 4, Week 12, and Week 24

  12. Plasma NfH

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 4, Week 12, and Week 24

  13. Plasma CHI3L1

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 4, Week 12, and Week 24

  14. Plasma Serpina1

    Time frame: Week -12, Week -8, Week -4, Week 0, Week 4, Week 12, and Week 24

  15. Exfoliated cells in cerebrospinal fluid (CSF): p-TBK1

    Time frame: Week 0 and Week 4 (optional)

  16. Exfoliated cells in cerebrospinal fluid (CSF): nuclear p-NF-κB

    Time frame: Week 0 and Week 4 (optional)

  17. Peripheral blood PBMC: p-mTOR

    Time frame: Week 0, Week 4, Week 12, and Week 24

07

Study locations

No study locations are listed for this record.

08

References and documents

Individual participant data

Plan to share: No

No publications or documents are linked to this record.

09

Updates

1 registry update since Sep 25, 2026
Registered
First appeared on the registry. No changes since
Oct 15, 2026
Show all 1 update
  1. Oct 15, 2026
    First appeared on the registry

From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗

10

Registry details

Key details

Study ID
NCT07875972
Lead sponsor
Liu Qing
Responsible party
Liu Qing (Chief Physician, Peking Union Medical College Hospital) — Sponsor-investigator
First posted
Oct 15, 2026
Start date
Oct 2026 (estimated)
Primary completion
Sep 2028 (estimated)
Completion
Oct 2028 (estimated)
Last update
Oct 15, 2026

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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